This invention provides a process for preparing intermediates useful in the preparation of tricyclic compounds known as inhibitors of farnesyl protein transferase. In particular, the compounds prepared by the process of this invention are useful as chiral intermediates in the preparation of chiral compounds that are FPT inhibitors such as those disclosed in PCT Publication No. WO97/23478, published Jul. 3, 1997.
Over the last few decades a number of enantioselective carbon-carbon bond forming reactions have been developed that fall into two distinct groups--those that involve alkylations of a covalently bonded chiral precursor and those that use a non-covalently bonded chiral auxiliary. Examples of the former include Evan's oxazolidinone system, Meyer's oxazoline system and Enders' RAMP/SAMP systems. (See Evans, D. A., et al., Encyclopedia of Reagents for Organic Synthesis; Wiley: Chichester, 1995, Vol. 1, p. 345; Gant, T. G.; Meyers, A.I. Tetrahedron 1994, 50, 2297; and Enders, D. et al, Liebigs Ann. 1995, 1127.) Examples of the latter, include alkylations of stabilized anions of ketones, imines, amino acid derived Schiff bases, N-alkyl carbamates and O-alkyl carbamates that are stabilized using non-covalently bonded chiral alkaloid bases or chiral lithium bases. (See, e.g., Hughes, D. L., et al, J. Org. Chem. 1987, 52, 4745.; Sato, D. et al, Tetrahedron 1997, 53, 7191; Koga, K. Pure & Appl. Chem. 1994, 66, 1487; Tomioka, K. et al, Chem. Pharm. Bull. 1989, 37, 1120; O'Donnell, M. J., et al, Tetrahedron 1994, 50, 4507; Weisenburger, G. A. et al, J. Am. Chem. Soc. 1996, 118, 12218; Gallagher, D. J. et al, J. Am. Chem. Soc. 1996, 118, 11391; and Hoppe, D. et al, Pure & Appl. Chem. 1996, 68, 613.) These reactions are similar in that the anion that is generated and alkylated has an adjacent carbonyl-type stabilizing group such as a ketone, imine or hydrazone. There have been few examples of a non-carbonyl type group stabilized anion. Gawley reported that an .alpha.-aminoorganolithium anion generated from a chiral stannane precursor is configurationally stable, and although alkylation with primary alkyl halides affords products with excellent enantioselectivity in certain cases, the fact that the chiral stannane precursor must be resolved detracts from this procedure. (See Gawley, R. E., et al, J. Org. Chem. 1995, 60, 5763.) Noyori et al. reported that silylation and carboxylation of the anion of the ethyl benzene/(-)-sparteine complex proceeds in .apprxeq.30% enantiomeric excess (e.e.) with low yields and significant amounts of reaction on the aromatic nucleus was also observed. (See Nozaki, H.; Aratani, T.; Toraya, T.; Noyori, R. Tetrahedron 1971, 27, 905.) White et al. reported that methylation of a 2-methylpyridine/(-)-sparteine complex proceeds in 20% e.e. and 64% yield. (See Papasergio, R. I.; Skelton, B. W.; Twiss, P.; White, A. H.; Raston, C. L. J. Chem. Soc. Dalton Trans. 1990, 1161.) Hoppe et al. reported that acylation of an indenine system (allylic anion) proceeded in &gt;95% ee with 52-79% yields. (See Hoppe, I. et al, Angew. Chem. Int. Ed. Engl. 1995, 34, 2158.)
We have now discovered a process for the enantioselective alkylation of non-ketone/amide/carbamate/imine benzyl type methylene compounds utilizing a chiral amino alcohol as a chiral ligand that results in high e.e. and high yield of intermediates useful for preparing the chiral FPT inhibitors discussed above.